Stroke is a leading cause of death and disability in the USA, yet widely effective treatments remain elusive and, except for a lengthy program of rehabilitation, no effective treatment for cerebral ischemic stroke is available. Therefore, there s a critical need in new therapeutic approaches which can maximally preserve ischemic penumbra and facilitate functional recovery. In the last two decades substantial efforts have been invested in developing anti-stroke medicine, but these efforts have not resulted in clinically-efficacious therapies for stroke. These failures highlight the need for development of new therapeutic ideas and approaches for prevention of neuronal injury secondary to ischemia and stroke. Among possible strategies, effective post-stroke treatments with broad therapeutic windows are likely to be the most valuable because of the unexpected nature of stroke. The existing literature and preliminary data presented indicate that activation of 7 nicotinic acetylcholine receptors (nAChRs) can significantly reduce brain injury and neurological deficits caused by ischemic injury. A novel therapeutic paradigm has been introduced that converts endogenous choline/ACh into potent therapeutic agents in cerebral ischemia by inhibiting 7 nAChR desensitization using Type-II positive allosteric modulators (i.e. PAMs-II), such as PNU-120596. Our preliminary data demonstrate that PNU-120596 administered intravenously up to 6 hours after the onset of focal cerebral ischemia significantly reduces infarct volume and improves neurological function in a middle cerebral artery occlusion (MCAO) model of cerebral ischemic stroke in rats and suggest that novel PAM-II agents represent a novel therapeutic opportunity in cerebral stroke. The path for discovery and proof-of-concept phases includes: A) synthesis of novel candidate molecules with appropriate calcium flux activity, stability, selectivity, solubility and drug-like characteristics for eventual use in in vivo efficacy studies;and B) a detailed functional activity assessment of PAM-II candidate profiles in acute rat brain slices We expect to identify novel leads with suitable drug-like properties for testing this novel concept in the context of a new therapy for cerebral ischemic stroke.